Process for preparing a pharmaceutically active compound

ABSTRACT

In particular, rizatriptan or a pharmaceutically acceptable salt thereof, which includes a) Preparation of the diazonium salt of aniline hydrochloride (II); followed by reduction and acidification to give the hydrazine (III); b) reaction in situ of the hydrazine hydrochloride (III) with α-keto-δ-valerolactone, to give the hydrazone (IV); c) Fischer indole reaction of the hydrazone (IV), to give the pyranoindolone (V), optionally followed by a hydrolysis reaction to give (VI); d) Transesterification of (V) or esterification of its hydrolysis product (VI), to give (VII), where R means straight or branched C1-C4 alkyl chain; e) Conversion of the hydroxyl group of (VII) into dimethylamino, to give the indolecarboxylate (VIII), where R has the meaning defined above; f) Saponification of the 2-carboalkoxy group of (VIII) to give indolecarboxylic acid (IX); and g) Decarboxylaton of the indolecarboxylic acid (IX) to give rizatriptan and, eventually, to obtain a pharmaceutically acceptable salt thereof. The invention also relates to synthesis intermediates to obtain rizatriptan.

FIELD OF THE INVENTION

This invention relates to a new process for preparing a pharmaceuticallyactive compound. In particular, it relates to a process for preparingrizatriptan.

BACKGROUND OF THE INVENTION

Patent EP 497512 describes derivatives of imidazole, triazole andtetrazole which act on the 5-HT receptor. Notable among them is thecompound 3-[2-(dimethylamino)ethyl]-5-(1,2,4-triazol-1-ylmethyl)-indole,of formula (I):

This compound is known by the INN rizatriptan and is marketed as ananti-migraine product.

The aforesaid European patent describes the preparation of rizatriptanby Fischer indole synthesis, using the corresponding phenylhydrazine andan aldehyde. The method described in that patent nevertheless has thefollowing disadvantages: it requires several steps of columnpurification and has an overall yield of only 11%.

Other processes for preparing rizatriptan were described subsequently.

On the one hand, preparation of the intermediate(4-[1,2,4]triazol-1-1-ylmethyl-phenyl)-hydrazine is optimised byInternational Patent Application WO 94/02476. Conversion of thisintermediate into rizatriptan is carried out by Fisher indole synthesis,in the same way as in the preceding patent. The yield for obtainingintermediate is improved by said process. The end product neverthelesscontinues to have the disadvantage of requiring a column purificationstep, so that it is not cost-effective to carry out the process atindustrial scale.

As well, International application WO 95/32197 describes a process forpreparing the product sought, by palladium-catalysed coupling ringclosure of 3-iodine-4-aminobenzyl-triazol with a suitably protectedbutynol derivative to the corresponding tryptophol followed byconversion of the hydroxyethyl moiety to dimethylaminoethyl. Althoughthis process does not require column purification, it has thedisadvantage of using a palladium catalyst which makes the process moreexpensive, while also using highly toxic reagents such as iodinechloride and highly flammable ones such as n-butyl lithium.

Finally, application WO 98/06725 describes the preparation of 2-silylprotected indoles, by palladium-catalysed cross-coupling reaction ofhaloanilines with acylsilanes, and preparation of the product sought bydeprotection of these intermediates so obtained. This process also hasthe disadvantage of using a palladium catalyst which makes the processmore expensive, while it also uses highly flammable reagents such asn-butyl lithium.

DESCRIPTION OF THE INVENTION

A first aspect of this invention is to provide a new process forpreparing rizatriptan or a pharmaceutically acceptable salt thereof,which includes the following steps:

a) Preparation of the diazonium salt of the aniline hydrochloride offormula (II)

followed by reduction and acidification to give the hydrazine of formula(III):

b) In situ reaction of the hydrazine hydrochloride of formula (III) withα-keto-δ-valerolactone to give the hydrazone of formula (IV):

c) Fischer indole synthesis of the hydrazone of formula (IV) to give thepyranoindolone of formula (V):

optionally, followed by a hydrolysis reaction to provide the product offormula (VI):

d) Transesterification of the compound of formula (V) or esterificationof its hydrolysis product of formula (VI), to provide a compound offormula (VII):

in which R represents a straight or branched C1-C4 alkyl chain;

e) Conversion of the hydroxyl group of the compound of formula (VII)into dimethylamino, to give the indolecarboxylate of formula (VIII):

in which R has the same meaning defined above;

f) Saponification of the 2-carboalkoxy group of the compound of formula(VIII), to provide the indolecarboxylic acid of formula (IX):

g) Decarboxylation of the indolecarboxylic acid of formula (IX), toprovide rizatriptan and,

eventually, the preparation of a pharmaceutically acceptable saltthereof.

The process for preparing rizatriptan object of this invention has theadvantages compared with the prior art of not requiring expensivecatalysts or highly toxic or highly flammable reagents, as well asinvolving no steps of column purification, which makes it a processsuitable for carrying out at industrial scale.

Following, each of the steps of the general process for preparingrizatriptan will be described in more detail.

Preparation of the diazonium salt of the aniline hydrochloride offormula (II) is carried out by treating this compound with sodiumnitrite and hydrochloric acid at low temperature. Subsequent reductionthereof is effected with an alkaline metal sulphite followed byacidification to give the hydrazine of formula (III).

Reaction of the hydrazine hydrochloride of formula (III) withα-ketovalerolactone is carried out in aqueous medium at a temperaturebetween 10° C. and 100° C., at a pH between 0.1 and 4, preferably atpH=1.

Steps a), b) and c) are preferably carried out as a “one pot” reaction,that is, without isolating the intermediates. In this case theindolisation reaction of the hydrazone of formula (IV) is carried out inthe solution resulting from step b), i.e. in aqueous medium, at a pHbetween 0.1 and 4, and at a temperature between 40° C. and 100° C.,preferably between 70° C.-80° C., and the hydrolysis reaction is thencarried out in situ by addition of alkaline hydroxide, preferablyaqueous sodium hydroxide, to give the compound of formula (VI), which isseparated by conventional methods.

Alternatively, after steps a) and b) the compound of formula (IV) can beisolated by conventional methods. In this case Fischer indole synthesisof the hydrazone of formula (IV) is carried out under conditions similarto those described in patent GB 1189064 for preparingcarboalkoxy-indoles. It is thus preferably carried out in a solution ofdry hydrogen chloride in acetic acid or in a C1-C4 alcohol (such asmethanol, ethanol, etc.). The reaction can be carried out at atemperature between 0° C. and 80° C., preferably at room temperature.Following the indolisation reaction the pyranoindolone of formula (V)can be isolated by conventional methods.

The transesterification or esterification reaction of step d) can thenbe carried out in an alcoholic solution, preferably methanol, and in thepresence of an acid, preferably methanesulphonic acid. The product isisolated by conventional methods.

Conversion of the hydroxyl group of the compound of formula (VII) into adimethylamino group is carried out preferably by substituting thehydroxyl group by a leaving group X and subsequent substitution reactionof the leaving group X with dimethylamine. Preferably, X is a halogenatom, a mesylate group (OMs) or a tosylate group (OTs).

The substitution of the hydroxyl group of the compound of formula (VII)by a leaving group X can be carried out by reacting it with mesylchloride or tosyl chloride or by replacing said hydroxyl by a halogen,using conventional halogenation reagents. When X=OTs, the reaction iscarried out in a suitable solvent, such as toluene, in the presence ofpyridine and using 4-(dimethylamino)pyridine as catalyst. When X=OMs,the reaction is carried out in a suitable solvent, such astetrahydrofuran, in the presence of triethylamine as catalyst. Thereaction can be carried out at a temperature between 0° C. and 50° C.,preferably at room temperature. The product is isolated by conventionalmethods.

In the case of the tosylates, the substitution reaction of the leavinggroup X with dimethylamine takes place under particularly gentleconditions. This reaction is carried out in an alcoholic solution or inan aqueous solution, at a temperature between 0° C. and 100° C.,preferably between 40° C. and 80° C. The product is isolated byconventional methods.

The saponification of the 2-carboalkoxy group of the compound of formula(VIII) is carried out in alkaline medium, preferably in an alcoholicsolution of potassium hydroxide, and at a temperature between 20° C. and100° C., preferably at reflux temperature. The product is isolated byconventional methods.

The decarboxylation of the indolecarboxylic acid of formula (IX) iscarried out in the presence of an inert solvent of high boiling pointand a suitable catalyst, in an inert atmosphere and at a temperaturebetween 180° C. and 250° C. Preferably, the solvent is quinoline or amixture of quinoline and an organic solvent such as triethylene glycoldimethyl ether, diphenyl ether, etc. Catalysts can be chosen frompowdered copper, cuprous oxide, cuprous chloride, cupric chromite,copper pentafluorophenyl or the cupric salt of the compound of formula(IX) used in a molar proportion between 5% and 10% in relation to thecompound of formula (IX). The inert atmosphere can be created by drynitrogen stream. The reaction is preferably carried out at 200° C. Theproduct is isolated by conventional methods.

The initial products can be obtained as indicated below.

The aniline hydrochloride of formula (II) can be obtained by reductionof the corresponding nitro derivative, as described in European patentEP 497512.

α-keto-δ-valerolactone can be obtained by decarboxylation ofα-ethoxalyl-γ-butirolactone in 2N H₂SO₄ at reflux.

A second aspect of the present invention is the synthesis intermediateof formula (IV):

A third aspect of the present invention is the synthesis intermediate offormula (V):

A fourth aspect of the present invention is the synthesis intermediateof formula (VI):

A fifth aspect of the present invention is a synthesis intermediate offormula (VII):

in which R represents a straight or branched C1-C4 alkyl chain.

A sixth aspect of the present invention is a synthesis intermediate offormula (VIII):

in which R represents a straight or branched C1-C4 alkyl chain.

A seventh aspect of the present invention is the synthesis intermediateof formula (IX):

The aforesaid synthesis intermediates of formula (IV), (V), (VI), (VII),(VIII) and (IX) are useful for the synthesis of rizatriptan, althoughtheir use for synthesis of other products likewise forms part of thescope of protection of this invention.

The steps described above in the general process for providingrizatriptan can therefore be considered independent processes forpreparing the intermediate synthesis products, isolating theintermediate product where necessary.

There follows a description of the steps of the general process asindependent procedures for preparing the synthesis intermediates.

-   -   A first process relates to preparation of the intermediate of        formula (IV) by reaction of the hydrazine hydrochloride of        formula (III) with α-keto-δ-valerolactone, in accordance with        step b) of the first aspect of the invention.    -   A second process relates to preparation of the intermediate of        formula (V) by Fischer indole synthesis of the hydrazone of        formula (IV), in accordance with step c) of the first aspect of        the invention.    -   A third process relates to preparation of the intermediate of        formula (VI) by Fischer indole synthesis of the hydrazone of        formula (IV) followed by the step of hydrolysis, in accordance        with step c) of the first aspect of the invention.    -   a fourth process relates to preparation of the intermediate of        formula (VII) by transesterification of the compound of        formula (V) or esterification of its hydrolysis product of        formula (VI), in accordance with step d) of the first aspect of        the invention.    -   A fifth process relates to preparation of the intermediate of        formula (VIII) by conversion of the hydroxyl group of the        intermediate of formula (VII) in dimethylamine, in accordance        with step e) of the first aspect of the invention.    -   A sixth process relates to preparation of the intermediate of        formula (IX) by saponification of the 2-carboalkoxy group of the        intermediate of formula (VIII), in accordance with step f) of        the first aspect of the invention.

Outlined below by way of explanation are the following non-restrictiveexamples of the invention.

EXPERIMENTAL PART EXAMPLES OF SYNTHESIS Example 13-(2-Hydroxyethyl)-5-[1,2,4]triazol-1-ylmethyl-1H-indol-2-carboxylicacid

To a solution of 3 g (14.28 mmoles) of4-(1,2,4-triazol-1-ylmethyl)phenylamine hydrochloride in 6 ml of waterand 11.5 ml of concentrated HCl, cooled to 0° C., a solution of 1 g(14.5 mmoles) of sodium nitrite in 2 ml of water was added slowly,keeping the temperature below 0° C. The mixture was stirred at thistemperature for 15 minutes. The diazonium salt solution was then addedrapidly to a solution of 10.8 g (85.7 mmoles) of sodium sulphite in 21.5ml of water precooled to 0° C. under nitrogen atmosphere. The redsolution was stirred at 0° C. for 10 minutes and then left to reach 65°C. in 1 hour. It was stirred at 65° C. for 30 minutes, and 6 ml ofconcentrated HCl then added. The mixture was stirred at the sametemperature under nitrogen atmosphere for 1 hour and then left to coolto room temperature. To this solution was added a solution of 22.8mmoles of α-keto-δ-valerolactone(prepared by decarboxylation of 2.1 g(11.4 mmoles) of α-ethoxalyl-γ-butirolactone in 6.6 ml of 2N H₂SO₄ atreflux) and left under stirring at 70° C. for 7 hours. When that timehad elapsed the mixture was cooled to 40° C. and added to 17 ml of 20%NaOH aqueous solution and 6 ml of ethanol. The mixture was washed with(15×2 ml) of AcOEt. The aqueous phase was filtered through decalite andadjusted to pH 4 with 2.5 ml of concentrated HCl. The yellow solidprecipitated was filtered, washed with cold water and dried in a hot-airoven at 40° C. to constant weight, giving 3.5 g (85%) of the titlehydroxy acid as a yellow solid.

IR (KBr): 1133, 1238, 1511, 1555, 1672, 3278, 3535 cm⁻¹.

¹H-NMR (200 MHz, DMSO-d₆): 3.21 (t, J=7.2 Hz, 2H, CH ₂CH₂OH); 23.60 (t,J=7.2 Hz, 2H, CH₂CH ₂OH); 5.45 (s, 2H, CH₂₋benz.); 7.20 (dd, J=1.6 and8.4 Hz, 1H, ar); 7.37 (d, J=8.4 Hz, 1H, ar); 7.68 (d, s, 1H, ar); 7.97(s, 1H, tz); 8.65 (s, 1H, tz); 11.52 (s, 1H, NH-indole).

¹³C-NMR (200 MHz, DMSO-d₆): 28.5; 53.1; 61.9; 112.8; 119.7; 120.5;125.1; 125.3; 127.2; 127.8; 135.8; 144.0; 151.7; 163.5.

Example 23-(2-Hydroxyethyl)-5-(1,2,4-triazol-1-ylmethyl)-1H-indol-2-carboxylicacid methyl ester

2.7 ml (42 mmoles) of methanesulphonic acid were added to a suspensionde 6 g (21 mmoles) of the3-(2-hydroxyethyl)-5-[1,2,4]triazol-1-ylmethyl-1H-indol-2-carboxylicacid in 120 ml of methanol. The mixture was left under stirring atreflux temperature for 3 hours. The solvent was evaporated to drynessunder reduced pressure, the residue dissolved with 20 ml of a saturatedbicarbonate solution and extracted 3 times with ethyl acetate. Thecombined organic phases were dried and evaporated to dryness, and theevaporated solid recrystallised from isopropyl alcohol/heptane to give5.9 g (93%) of the title ester as a yellow crystalline solid.

M.p. 177.8-179.5° C.

IR (KBr): 1704, 3230 cm⁻¹.

¹H-NMR (200 MHz, DMSO-d₆): 3.19 (m, 2H, CH ₂CH₂OH); 3.58 (m, 2H, CH₂CH₂OH); 3.86 (s, 3H, CH₃); 4.71 (t, J=5.2 Hz, 1H, OH); 5.45 (s, 2H,CH₂-benz.); 7.22 (d, J=8, 4 Hz, 1H, ar); 7.37 (d, J=8.4 Hz, 1H, ar);7.68 (s, 1H, ar); 7.95 (s, 1H, tz); 8.64 (s, 1H, tz); 11.62 (s, 1H,NH-indole).

¹³C-NMR (200 MHz, DMSO-d₆): 29.1; 52.3; 53.4; 62.3; 113.4; 121.1; 124.5;126.0; 128.0; 128.2; 136.6; 144.6; 152.3; 162.7.

Example 33-[4-(1,2,4-Triazol-1-ylmethyl)phenyl-hidrazono]tetrahydropyran-2-one a.(4-[1,2,4]Triazol-1-ylmethylphenyl)hydrazine hydrochloride

To a solution of 1.5 g (7.1 mmoles) of4-(1,2,4-triazol-1-ylmethyl)phenylamine hydrochloride in 3.75 ml ofwater and 6.3 ml of concentrated HCl, cooled to 0° C., was added slowlya solution of 0.5 g (7.2 mmoles) of sodium nitrite in 2.6 ml of water,keeping the temperature below 0° C. The mixture was stirred at thistemperature for 15 minutes. Once this time had elapsed the solution ofthe diazonium salt was added rapidly to a solution of 5.37 g (42.6mmoles) of sodium sulphite in 19 ml of water precooled to 0° C. undernitrogen atmosphere. The red solution was stirred at 0° C. for 10minutes and then left to reach 65° C. in 1 hour. It was stirred at 65°C. for 30 minutes, and 5 ml of concentrated HCl were then added. Themixture was stirred at the same temperature under nitrogen atmospherefor 3 hours and then left to cool to room temperature.

b. 3-[4-(1,2,4-Triazol-1-ylmethyl)phenylhidrazono]tetrahydropyran-2-one

To the solution obtained in the previous section is added a solution of11.4 mmoles of α-keto-δ-valerolactone(prepared by decarboxylation of 2.1g (11.4 mmoles) of α-ethoxalyl-γ-butirolactone in 3.15 ml of 2N H₂SO₄ atreflux) and left under stirring at room temperature for 12 hours. Oncethis time had elapsed the mixture was cooled to 0° C. and adjusted to pH6 with a 20% NaOH solution, precipitating a yellow solid which wasfiltered, washed with water and dried in hot-air oven at 40° C., to givea yellow solid which was crystallised from ethanol/water to give 1.72 g(85%) of the title hydrazone as a yellow solid.

M.p. 213.6-215.0° C.

IR (KBr): 1122 cm⁻¹, 1244 cm⁻¹, 1505 cm⁻¹, 1550 cm⁻¹, 1705 cm⁻¹.

¹H-NMR (200 MHz, DMSO-d₆): 1.98 (m, 2H, γ-lactone); 2.59 (m, 2H,β-lactone); 4.27 (m, 2H, γ-lactone); 5.31 (s, 2H, CH₂₋benz.); 7.25 (s,4H, ar); 7.96 (s, 1H, tz); 8.61 (s, 1H, tz); 10.08 (s, 1H,NH-hydrazone).

¹³C-NMR (200 MHz, DMSO-d₆): 21.3; 24.5; 52.0; 67.5; 114.2; 129.0; 129.2;131.2; 144.1; 151.8; 162.2.

Example 46-(1,2,4-Triazol-1-ylmethyl)-4,9-dihydro-3H-pyrano[3,4-b]indol-1-onehydrochloride

1.7 g (5.9 mmoles) of3-[4-(1,2,4-Triazol-1-ylmethyl)phenylhydrazono]tetrahydropyran-2-onewere added to a stirred solution of 15 ml absolute ethanol saturatedwith dry hydrogen chloride. The stirring was continued at roomtemperature for 16 hours. 5 ml of water/ice were added to the reactionmixture, and the mixture then stirred at 0° C. for 20 min. Theprecipitate was filtered, washed with ethanol/water and dried in hot-airoven at 40° C., to give 1.65 g (92%) of the title compound as a whitesolid.

M.p. 231.1-233.8° C.

IR (KBr): 1705 cm⁻¹.

¹H-NMR (200 MHz, DMSO-d₆): 3.09 (t, J=6.0 Hz, 2H, γ-lactone); 4.61 (t,J=6.0 Hz, 2H, δ-lactone); 5.51 (S, 2H, CH₂-benz.), 7.32 (d, J=8.6 Hz,1H, ar); 7.43 (d, J=8.6 Hz, 1H, ar); 7.70 (s, 1H, ar); 8.21 (s, 1H, tz);9.00 (s, 1H, tz); 12.04 (s, 1H, NH-indole).

¹³C-NMR (200 MHz, DMSO-d₆): 21.5; 53.8; 69.9; 113.9; 121.8; 123.1;123.7; 124.7; 127.1; 128.1; 138.5; 144.1; 151.0; 161.0.

Example 53-(2-Hydroxyethyl)-5-(1,2,4-triazol-1-ylmethyl)-1H-indol-2-carboxylicacid methyl ester

To a suspension of 2.5 g (8.2 mmoles) of the6-(1,2,4-triazol-1-ylmethyl)-4,9-dihydro-3H-pyrano[3,4-b]indol-1-on ahydrochloride in 50 ml of methanol were added 0.66 ml (10.2 mmoles) ofmethanesulphonic acid. The mixture was left under stirring at the refluxtemperature for 4 hours. The solvent was evaporated to dryness underreduced pressure, the residue dissolved with 10 ml of a saturatedbicarbonate solution and extracted 3 times with ethyl acetate. Thecombined organic phases were dried and evaporated to dryness and theevaporated solid recrystallised from isopropyl alcohol/heptane to give2.3 g (94%) of the title ester as a yellow crystalline solid.

M.p. 177.8-179.5° C.

IR (KBr): 1704 cm⁻¹, 3230 cm⁻¹.

¹H-NMR (200 MHz, DMSO-d₆): 3.19 (m, 2H, CH ₂CH₂OH); 3.58 (m, 2H, CH₂CH₂OH); 3.86 (s, 3H, CH₃); 4.71 (t, J=5.2 Hz, 1H, OH); 5.45 (s, 2H,CH₂-benz.); 7.22 (d, J=8.4 Hz, 1H, ar); 7.37 (d, J=8.4 Hz, 1H, ar); 7.68(s, 1H, ar); 7.95 (s, 1H, tz); 8.64 (s, 1H, tz); 11.62 (s, 1H,NH-indole).

¹³C-NMR (200 MHz, DMSO-d₆): 29.1; 52.3; 53.4; 62.3; 113.4; 121.1; 124.5;126.0; 128.0; 128.2; 136.6; 144.6; 152.3; 162.7.

Example 63-[2-Toluen-4-sulphonyloxy)ethyl]-5-(1,2,4-triazol-1-ylmethyl)-1H-indol-2-carboxylicacid methyl ester

To a stirred suspension of 1.3 g (4.3 mmoles) of3-(2-hydroxyethyl)-5-(1,2,4-triazol-1-ylmethyl)-1H-indol-2-carboxylicacid methyl ester in 7.1 ml of dichloromethane were added 0.71 ml ofpyridine, 1.3 g (6.9 mmoles) of tosyl chloride and 53 mg (0.43 mmoles)of dimethylaminepyridine and the stirring then continued at roomtemperature for 20 hours. The reaction mixture was then poured onto 5 mlof 3N HCl precooled to 0° C. and extracted three times with 20 ml ofdichloromethane. The combined organic phases were then washed withbrine, dried on anhydrous sodium sulphate and the solvent evaporated todryness. The evaporated solid was crystallised from isopropyl alcohol togive 1.9 g (97%) of the title tosylate as a white solid.

IR (KBr): 1255 cm⁻¹, 1438 cm⁻¹, 1511 cm⁻¹, 1550 cm⁻¹, 1700 cm⁻¹.

¹H-NMR (200 MHz, DMSO-d₆): 2.34 (s, 3H, CH₃); 3.30 (t, J=6.4 Hz, 2H, CH₂CH₂Ots); 3.81 (s, 3H, OCH₃); 4.23 (t, J=6.4 Hz, 2H, CH₂CH ₂Ots); 5.43(s, 2H, CH₂-benz.); 7.23 (m, 3H, ar); 7.36 (d, J=8.4 Hz, 1H, ar); 7.45(d, J=8.6 Hz, 2H, ar); 7.58 (s, 1H, ar); 8.00 (S, 1H, tz); 8.68 (s, 1H,tz); 11.74 (s, 1H, NH-indole).

¹³C-NMR (200 MHz, DMSO-d₆): 14.3; 25.6; 44.7; 52.9; 60.6; 113.0; 118.9;119.2; 120.4; 125.5; 125.6; 127.1; 127.2; 127.3; 127.8; 129.8; 135.9;144.7; 161.5.

Example 73-(2-Dimethylaminoethyl)-5-[1,2,4-triazol-1ilmethyl]-1H-indol-2-carboxylicacid methyl ester

1.2 g (2.6 mmoles) of3-[2-Toluen-4-sulphonyloxy)ethyl]-5-(1,2,4-triazol-1-ylmethyl)-1H-indol-2-carboxylicacid methyl ester were dissolved with 14 ml of a 2N dimethylaminesolution in methanol. The solution was stirred at 50° C. for 20 hours ina closed reactor. The solvent was evaporated to dryness, the residuedissolved in 20 ml of 3N HCl and washed three times with 10 ml ofdichloromethane. The washed aqueous phase was cooled and adjusted to pH12 with a 40% sodium hydroxide solution and extracted three times with20 ml of dichloromethane. The combined organic phases were washed with20 ml of brine and dried on anhydrous sodium sulphate. The solvent wasevaporated to dryness to give 800 mg (94%) of the title compound. Theproduct was recrystallised from ethanol to give a white solid.

M.p. 151.7-153.0° C.

IR (KBr): 1694 cm⁻¹.

¹H-NMR (200 MHz, DMSO-d₆): 2.12 (S, 6H, N(CH₃)₂); 2.47 (m, 2H, CH₂CH₂N); 3.15 (t, J=7.6 Hz, 2H, CH₂CH ₂N); 3.86 (s, 3H, OCH₃); 5.46 (s,2H, CH₂-benz.); 7.20 (d, J=8.6 Hz, 2H, ar); 7.37 (d, J=8.6 Hz, 2H, ar);7.64 (s, 1H, ar); 7.96 (s, 1H, tz); 8.65 (s, 1H, tz); 11.65 (s, 1H,NH-indole).

¹³C-NMR (200 MHz, DMSO-d₆): 22.2; 44.9; 51.7; 52.8; 59.9; 112.9; 120.2;121.4; 123.7; 125.4; 127.1; 127.5; 136.0; 144.0; 151.7; 162.0.

Example 83-(2-Hydroxyethyl)-5-[1,2,4-triazol-1-ylmethyl]-1H-indol-2-carboxylicacid

To a solution of 705 mg (12.6 mmoles) of KOH in 15 ml of ethanol wasadded 1.4 g (4.2 mmoles) of3-(2-dimethylaminoethyl)-5-[1,2,4-triazol-lilmethyl]-1H-indol-2-carboxylicacid methyl ester, and the resulting solution stirred at refluxtemperature for 1 hour. The solvent was cooled and evaporated todryness. The residue was redissolved in 6 ml of water and washed threetimes with 10 ml of dichloromethane. The aqueous solution was cooled to5° C. and adjusted to pH 6 with glacial acetic acid and stirred at thistemperature for 30 minutes. The solvent was concentrated to one half, 15ml of isopropyl alcohol added, the mixture stirred for 1 hour at 0° C.and the precipitated solid filtered and dried in hot-air oven at 40° C.,to give 1.25 g (94%) of the title acid as a white crystalline solid.

M.p. 231.4° C. (dec.).

IR (KBr): 1594 cm⁻¹, 1361, 1333 cm⁻¹.

¹H-NMR (200 MHz, D₂O): 2.85 (s, 6H, N(CH₃)₂), 3.29 (s, 4H, CH ₂CH ₂N),5.31 (s, 2H, CH₂), 7.23 (d, J=8.6 Hz, 1H, ar), 7.37 (d, J=8.6 Hz, 1H,ar), 7.46 (s, 1H, ar), 8.00 (s, 1H, tz), 8.42 (s, 1H, tz).

¹³C-NMR (200 MHz, D₂O): 22.6; 46.0; 56.3; 61.5; 115.6; 115.7; 122.1;127.2; 129.1; 129.9; 134.0; 137.5; 146.9; 154.1; 172.0.

Example 9N,N-Dimethyl-2-[5-(1,2,4-triazol-1-ylmethyl)-1H-indol-3-il]ethylamine

700 mg (2,2 mmoles) of3-(2-hydroxyethyl)-5-[1,2,4-triazol-1-ylmethyl]-1H-indol-2-carboxylicacid was suspended in 7 ml of dry quinoline. 14 mg of cuprous oxide wasadded and the stirred suspension heated, under dry nitrogen stream, to200° C. The reaction mixture was kept at this temperature until no moreCO₂ was released (15-20 min.). It was left to cool to room temperatureand the reaction mixture was filtered through decalite. The filtrate wasconcentrated by vacuum distillation of the solvent, providing a residuewhich was dissolved with a succinic acid solution and washed three timeswith 10 ml of dichloromethane. The washed aqueous phase was cooled andadjusted to pH 12 with a 40% sodium hydroxide solution and extractedthree times with 20 ml of dichloromethane. The combined organic phaseswere dried on anhydrous sodium sulphate and evaporated to dryness. Theresidue was recrystallised from heptane/isopropyl acetate to give 510 mg(86%) of rizatriptan as a white solid.

M.p. 120-122° C.

¹H-NMR (200 MHz, CDCl₃): 2.33 (s, 6H, N(CH₃)₂); 2.62 (t, J=8.2 Hz, 2H,CH ₂CH₂N); 2.88 (t, J=8.2 Hz, 2H, CH₂CH ₂N); 5.41 (s, 2H, CH₂-benz.);7.06 (m, 2H, ar); 7.31 (d, J=8.4 Hz, 1H, ar); 7.55 (s, 1H, ar); 7.96 (s,1H, tz); 7.99 (s, 1H, tz); 8.59 (ba, 1H, NH-indole).

¹³C-NMR (200 MHz, CDCl₃): 23.5; 45.4; 54.5; 60.1; 111.8; 114.4; 119.2;122.2; 122.6; 124.8; 127.7; 136.1; 142.7; 151.8.

Example 10N,N-Dimethyl-2-[5-(1,2,4-triazol-1-ylmethyl)-1H-indol-3-il]ethylamine.Benzoate

A solution of 147 mg (1.2 mmoles) of benzoic acid in 1 ml of isopropylacetate was added slowly to a solution of 300 mg (1.1 mmoles) of therizatriptan base in 2.6 ml of isopropyl alcohol. The mixture was stirredat room temperature for 30 minutes and evaporated to dryness, and theresidue recrystallised from ethanol to give 345 mg (80%) of rizatriptanbenzoate as a white crystalline solid.

M.p. 180-182° C.

IR (KBr): 1605 cm⁻¹, 1566 cm⁻¹.

¹H-NMR (200 MHz, D₂O): 2.89 (s, 3H, N(CH₃)₂), 313 (t, J=7.6 Hz, 2H, CH₂CH₂N), 3.37 (t, J=7,6 Hz, 2H, CH₂CH ₂N), 5.42 (s, 2H, CH₂-benz.), 7.15(dd, J=1.6 and 8.4 Hz, 1H, ar-indole), 7.31 (s, 1H, ar-indole), 7.48 (m,4H, ar), 7.59 (s, 1H, ar-indole), 7.90(d, J=8.2 Hz, 1H, ar-benz,), 8.03(s, 1H, tz), 8.48 (s, 1H, tz).

¹³C-NMR (200 MHz, D₂O): 22.9; 45.4; 56.4; 60.3; 111.3; 115.3; 121.0;125.1; 127.8; 128.6; 129.2; 131.0; 131.6; 134.0; 138.9; 139.0; 146.7;154.1; 178.4.

1. Process for preparing a pharmaceutically active compound,rizatriptan, or a pharmaceutically acceptable salt thereof, whichcomprises the following steps: a) Preparation of the diazonium salt ofthe aniline hydrochloride of formula (II)

followed by reduction and acidification to give the hydrazine of formula(III):

b) In situ reaction of the hydrazine hydrochloride of formula (III) withα-keto-δ-valerolactone, to give the hydrazone of formula (IV):

c) Fischer indole reaction of the hydrazone of formula (IV), to give thepyranoindolone of formula (V):

followed optionally by hydrolysis to give the product of formula (VI):

d) Transesterification of the compound of formula (V) or esterificationof its hydrolysis product of formula (VI), to give a compound of formula(VII):

where R represents a straight or branched C1-C4 alkyl chain; e)conversion of the hydroxyl group of the compound of formula (VII) intodimethylamino, to give the indolecarboxylate of formula (VIII):

where R has the same meaning as defined above; f) Saponification of the2-carboalkoxy group of the compound of formula (VIII), to give theindolecarboxylic acid of formula (IX):

g) Decarboxylation of the indolecarboxylic acid of formula (IX), to giverizatriptan, and eventually, the preparation of a pharmaceuticallyacceptable salt thereof.
 2. Process according to claim 1, wherein instep c) the indolisation is carried out in a solution of dry hydrogenchloride in a straight or branch C1-C4 alcohol chain.
 3. Processaccording to claim 1, wherein steps a), b) and c) are carried out as aone pot reaction.
 4. Process according to claim 1, wherein step c) iscarried out in aqueous acid medium and is followed by a hydrolysisreaction to give the product of formula (VI).
 5. Process according toclaim 1, wherein step e) is carried out in two steps: e-i) substitutionof the hydroxyl group of the compound of formula (VII) by a leavinggroup X; and e-ii) subsequent substitution reaction of the leaving groupX with dimethylamine to give the compound of formula (VIII).
 6. Processaccording to claim 5, wherein the leaving group X is selected from ahalogen atom, a mesylate group or a tosylate group.
 7. Process accordingto claim 1, wherein step d) is carried out in an alcoholic solution andin the presence of an acid.
 8. Process according to claim 1, wherein aSynthesis intermediate of formula (IV):


9. Process according to claim 1, wherein a Synthesis intermediate offormula (V):


10. Process according to claim 1, wherein a Synthesis intermediate offormula (VI):


11. Process according to claim 1, wherein a Synthesis intermediate offormula (VII):

where R represents a straight or branched C1-C4 alkyl chain.
 12. Processaccording to claim 1, wherein a Synthesis intermediate of formula(VIII):

where R represents a straight or branched C1-C4 alkyl chain.
 13. Processaccording to claim 1, wherein a Synthesis intermediate of formula (IX):